DLGAP 1 and NMDA receptor‐associated postsynaptic density protein genes influence executive function in attention deficit hyperactivity disorder

Objective To explore the association of DLGAP 1 gene with executive function ( EF ) in attention deficit hyperactivity disorder ( ADHD ) children. Method A total of 763 ADHD children and 140 healthy controls were enrolled. The difference of EF between ADHD and controls was analyzed using the analysis of covariance ( ANCOVA ), with IQ , sex, and age as covariates. Both the associations of SNP s with EF and three symptom traits of ADHD were conducted using an additive linear regression model by PLINK with the same covariates as ANCOVA . Results Compared with controls, children with ADHD showed poorer cognitive flexibility and inhibition. Two SNP s (rs2049161, p ‐value = 5.08e‐7, adjusted p ‐value = 1.63e‐4, rs16946051, p ‐value = 5.18e‐7, adjusted p ‐value = 1.66e‐4) survived multiple tests in Trail Making Test. Both SNP s also showed association with TOH (rs2049161, p  = 6.82e‐4, rs16946051, p  = 7.91e‐4). Set‐based analysis for gene DLGAP 1 and its functional pathway DLGAP 1‐ DLG 4‐ NMDA showed they were associated with cognitive flexibility at both gene ( p  = .0057) and pathway level ( p  = .0321). Furthermore, the gene and pathway also showed association with ADHD symptom score. The associated SNP s and their LD proxies were related to the expression of DLGAP 1 in medulla and frontal cortex. Conclusion Children with ADHD showed deficit in EF , especially, cognitive flexibility and inhibition. DLGAP 1 was associated with cognitive flexibility and plan, and the role of DLGAP 1 might be implemented through the complex of DLGAP 1‐ DLG 4‐ NMDA .